1. Field Of The Invention
The present invention relates to derivatives of aminocardenolides, to a process for their preparation and their therapeutic applications.
2. Description Of The Prior Art
It is well known that numerous natural substances derived from cardiotonic heterosides are used therapeutically for the treatment of cardiac disorders. The cardiotonic activity of the cardenolide-glycosides, especially, depends principally on the structure of the cardenolide part and on the nature of the sugar-containing chain attached at 3.beta.. Because of the low therapeutic activity of these natural substances, and the disadvantages which occur from their utilization, it seemed interesting to prepare compositions of similar structure possessing satisfactory cardiotonic activity together with low toxicity.
It was suggested that an appropriate substituent be attached in the 3 position of the cardenolide moiety, preferably at 3.beta. position. For example, French Pat. Nos. 2,085,722 and 2,111,705 describe cardenolide derivatives substituted at the 3.alpha. and 3.beta. positions by an amino or alkylamino group.
However, the preparation of such compositions, containing a substituent attached by a nitrogen atom at the 3 position of the cardenolide, becomes all the more difficult and delicate as the substituent is complex and itself comprises one or more functional groups. The preparation of such compositions must then be carried out in several steps, and it is necessary first of all to prepare the derivative of cardenolide substituted at the 3 position by an NH.sub.2 group, for example, by the action of hydroxylamine on an oxo-3 cardenolide to form an oxime which is reduced by hydrogen in the presence of a metallic catalyst. A primary amine can also be used to form a Schiff base which is then catalytically hydrogenated. This amino-3 cardenolide can then be used as an intermediate for the preparation of other compositions with substitution on the nitrogen atom.
These processes are difficult to bring about because of the large number of steps which they require and of the fragility of the cardenolide moiety, especially the lactone ring attached at the 17 position, of which saturation must be avoided by carefully monitoring the reduction step.